Diazine derivatives



Patented Mar. 2, 1943 I 1 UNITED STATES PATENT OFFICE DIAZINE DERIVATIVES New York Gaetano F. DAlelio, Pittsileld, Masa, assignor to General Electric Company, a corporation of No Drawing. Application December 12, 1941, Serial No. 422,721

16 Claims. (01. 260 -251) L R f N/ In the above formula n represents an integer and is at least 1 and not more than 2, Z represeats a member of the class consisting of oxygen and sulfur, Y represents a divalent carbocyclic radical, and R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and substituted hydrocarbon radicals, more particularly halo-hydrocarbon radicals. Since 11 represents an integer which is 1 or 2, it will be seen that the linkage of the hydroxycarbocyclic-carbamyl-alkyl or hydroxycarbocyclicthiocarbamyl-alkyl grouping to the sulfur atom in all cases will be alpha or beta to the hydroxycarbocyciic-carbamyl or -thiocarbamyl grouping. It also will be observed that linkage of the pyrimidyl grouping to the sulfur atom is through a carbon atom. a

Illustrative examples of radicals that R inthe above formula may represent are: aliphatic (e. g., methyl, ethyl, propyl, isopropyl, allyl, butyl,

secondary. butyl, isobutyl, butenyl, amyl, isoamyl, hexyl, etc.), including cycloaliphatic (e. g., cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, etc.) aryl (e. g., phenyl, diphenyl or xenyl, naphthyl, etc.) aliphatic-substituted aryl (e. g., tolyl, xylyl, ethylphenyl, propylphenyl, isopropylphenyl, allylphenyl, Z-butenylphenyl, tertiarybutylphenyl, etc.) aryl-substituted aliphatic (e. g., benzyl, phenylethyl, phenylisopropyl, cinnamyl, etc); and their homologues, as well as those groups with one or more of their hydrogen atoms substituted by, for example, a halogen. Specific examples of halogeno-substituted hydrocarbon radicals are chloromethyl, chloroethyl, chlorophenyl, dichlorophenyl, chlorocyclohexyl, ethyl chlorophenyl, phenyl chloroethyl, bromopropyl, bromoethyl, bromotolyl, etc. Preferably R in Formula I is hydrogen. However, there also may be produced in accordance with the present invention compounds, such, for instance, as those repsesented by the general formulas:

where n, Z, Y and R have the same meanings as given above with reference to Formula I.

Illustrative examples of divalent carbocyclic radicals which Y in Formulas I, II and III may represent are: divalent aryl, e. g., phenylene,

xenylene, naphthylene, eta; divalent aliphaticaryl, e. g., 2,5-tolylene, para(2,3-xylylene), etc.;

divalent cycloallphatic, e. g., cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, etc.: and their homologues, as well as those divalent carbocyclic radicals with one or more of their hydrogen atoms replaced by a substltuent, e. g., halogeno, amin acetyl, acetoxy, carboalkoxy, alkoxy, aryloxy, sulfamyl, alkyl, alkenyl, a hydroxy group or groups in addition to the single ---OH group shown in the above formulas, etc. Specific. examples of substituted divalent carbocyclic radicals are chlorophenylene, bromophenylene, ohloronaphthylene,

brcmonaphthylene, bromo 2,5-tolylene, chlorocyclopentylene, chlorocyclopentenylene, carbomethoxyphenylene, ethoxyphenylene, acetophenylene, acetoxyphenylene, bromocyclopentylene, aminophenylene, phenoxyphenyl'ene, sulfamylphenylene, methylphenylene (tolylene), allylphenylene, etc. Preferably Y is phenylene or methylphenylene.

The new compounds of this invention may be used, for example, as pharmaceuticals, plasticizers and as intermediates in the preparation of derivatives thereof such as hydrazo, hydrazino, carbazido, semicarbazidc, ureido, carbamyl, acyl, amidine, methylol, etc., derivatives of the individual compound embraced by Formula I. These new organic sulfides are especially valuable in the preparation of synthetic resinous compositions. Thus, they may be condensed with, for instance, aldehydes, including polymeric aldehydes and aldehyde-addition products,

to yield condensation products of particular utility in the plastics and coating arts. Such condensation products are more fully described and are specifically claimed in my copending application Serial No. 425,161, filed December 31, 1941, and assigned to the same assignee as the present invention. These new organic sulfides also may be compounded with rubber, both natural and synthetic, to modify the properties of the rubber.

Various methods may be employed to produce the, chemical compounds of this invention. I prefer to prepare them by a process which comprises effecting reaction between a diamino [(NHR) a] mercapto pyrimidine and a. hydroxycarbocyclic-carbamyl-aikyl halide (or a hydroxycarbocyclicthiocarbamyl-alkyl halide) in the presence of a hydrohalide acceptor, e. g., an alkali-metal hydroxide. When the starting components, proportions thereof and reaction conditions are such that the hydrogen atom of the -OH group of the hydroxycarbocyciic compound is replaced by the residue of the hydrohaiide acceptor, e. g., by an alkali metal, the hydroxy compound desired as a final product is obtained by treating this intermediate product with hydrochloric, hydrobromic, sulfuric or other suitable organic or inorganic acid in an amount Just sumcient to form the desired hydroxy derivative.

Illustrative examples of mercapto pyrimidines that may be used, depending upon the particular end-product desired, are:

2-mercapto 4-(3-buteny1amino) 6-isopropyiamino pyrimidine s Z-mercapto 4-amino fi-chloroxenylamino pyrimidine 2-mercapto 4-ethylphenylamino S-naphthyl 6 xylidino pyrimidine 2-mercapto i-isopropylanilino 5-benzyl 6-benzylamino pyrimidine Z-mercapto 4-phenethylamino 5-.(2'-butenyl) 6- cyciopentenylamino pyrimidine Z-mercapto 4,6-diamino 5-bromotolyl pyrimidine Z-mercapto 4-amino 5-phenylisopropyl 6-chiorocyciohexylamino pyrimidine 2-mercapto 4-isobutylamino G-bromonaphthylamino pyrimidine 2-miercapto 4,6-diamin0 5-phenylpropyl pyrimid no Z-mercapto 4-chlorobenzylamino 5-ch1orobutyl 6-bromoethylamino pyrimidine 2-mercapto i-amino 5-ethylchloropheny1 6-sec.-

butylamino pyrimidine 2-mercapto 4 pentylamino 6 cyclohexyiamino pyrimidine 2-mercapto 4-n-hexylamino 6-xenylamino pyrimidine 2-mercapto 4 cyclohexenylamino 6 naphthylamino pyrimidine z-mercapto' 4-amino 6-bromoethylamino pyrimidine Z-mercapto 4-amino B-methylamino py imidine 2-mercapto 4-aminoanilino 6-ethylphenylamino pyrimidine Z-mercapto 4-amino S-benzylamino pyrimidine Z-mercapto 4-chlorocyclopentyiamino 6-toiuido pyrimidine Illustrative examples of hydroxycarbocycliccarb'amyl-alkyl halides and hydroxycarbocyclicthiocarbamyl-alkyl halides that may be employed, depending upon the particular end-product sought, are:

Para-hydroxyphenyl-oarbamyl chloro methane Alpha-(para hydroxyphenyl carbamyl) beta chloro ethane Alpha-(meta-hydroxyphenyl carbamyl) alphachloro ethane Alpha-(para-hydroxyphenyl thiocarbamyl) alpha-chloro pentane Ortho-hydroxyphenyi-(methyl) -carbamyl bromo methane I Alpha-(4-hydroxynaphthyl- [1] -carbamyl) betachloro butene Alpha-(para-hydroxy chloro phenyl-carbamyl) alpha-ethyl beta-phenyl beta-bromo ethane Hydroxytolyl-carbamyi cyclopentyl chloro methane Hydroxytolyl-(butyl)-carbamyi bromo methane Para-hydroxyphenyl- (cyciopentyi) -thiocarbamyl chloro methane Para hydroxyphenyl (chloroethyl) carbamyl chloro methane -hydroxycyclohexyl- (phenyl) -carbamyi methane Alpha [para hydroxy chloro phenyl-(bromophenyD-thiocarbamyl] alpha-chlorocyclohexenyl beta-chloro ethane 3 hydroxycyclopentyl carbamyl toiyl chloro methane A1pha-[4-hydroxy 2-chloro cyclopentyl- (xenyl) carbamyl] alpha-chloroxylyl beta-chloro ethane Alpha-(para-hydroxyphenyi carbamyl) iodn omega-chloro pentane Hydroxycyclohexenyl (phenylisopropyl) carbamyi chlorocyclopentenyl chloro methane chloro alpha- Alpha [para hydroxyxenyl (isobutylphenyl) carbamyl] beta-naphthyl beta-bromo ethane Alpha-[para-hydroxy chloro phenyl-(isopentyl) thiocarbamyl] alpha-ethyl alpha-tolyl beta.-

phenyl beta-bromo propane Various hydrohalide acceptors may be employed. I meter to use a hydrohaiide acceptor that will react with the mercapto pyrimidine to form a water-soluble salt. Examples of such acceptors are the alkali-metal hydroxides, e. g., sodium hydroxide, potassium hydroxide, etc.; carbonates or inorganic bases, including the carbonates oi alkali-metals; organic amines such as tertiary amines, e. 3., trimethyl amine, triethyl amine, tributyl amine, pyridine, dimethyl aniline, quinoline, etc.; quaternary ammonium bases, e.

.presence of a suitable solvent or 2-chloro 2-bromo 4-cyclohexenylamino g., tetramethyl ammonium hydroxide, etc.; and the like.

The reaction between *the mercapto diamino pyrimidine and the hydroxycarbocyclic-carbamyl-alkyl halide (or hydroxycarbocyclic-thim, carbamyl-alkyl halide) may be carried out in any suitable manner, but preferably is effected in the mixture of $01- vents. Although various solvents and solvent mixtures may be employed, for economic reasons and because of their eminent suitability I prefer to use water or a mixture oi water and alcohol. The reaction may be carried out under a variety of temperature and pressure conditions, for instance at normal, sub-normal or at elevated temperatures and at atmospheric, subatmospheric or super-atmospheric pressures.

The new chemical compounds of this invention also may beprepared by a process which comprises eilecting reaction between a halogenated diamino pyrimidine and a hydroxy-, carbocyclic-carbamyl mercapto alkane (or a hydroxycarbocyclicthiocarbamyl mercapto kane) in the presence of a hydrohalide acceptor. This reaction preferably is carried out in the presence of an anhydrous solvent. An anhydrous solvent, e. g., alcohol, is desirable because one of the reactants, namely, the halogenated diamino pyrimidine, is hydrolyzable. The other conditions for preparing the compounds of the invention may be the same as described above with reference to the first-mentioned method of preparation. i

Illustrative examples oi halogenated diamino pyrimidines that may be used, depending upo the end-product desired, are:

Z-chloro 4,6-diamino pyrimidine 2-chloro 4,6-di-(methylamino) pyrimidine 2-chloro 4,6-di-(ani1ino) pyrimidine 2-bromo 4-amino G-ethylamino pyrimidine 2-chloro 4,6-di-(propylamino) pyrimidine 2-bromo 4,6-di-(methyiamino) b -methyi pyrimidine d-methylamino O-chloroethylamino pyrimidine 2-iodo 4,6-di-(anilino) fi-butyl pyrimidine 2-bromo 4-allylamino B-butylamino pyrimidine 2-chioro 4-isobutylamino G-cyclo'pentylamino pyrimidine Z-chloro 4-(3'-butenylamino) G-isopropylamino py midine 2-chloro 4 -amylamino fi-cyciohexylamino pyrim idine 2-chloro 4-amylamino 5-cyclopentyl d-xenylamino pyrimidine z-toluido 4-bromo o-cyclohexenyl G-amino pyrimidine iii-toluido 4-amino S-cyclohexenyl B-bromo pyrimidine) z-aliylamino l-chloro b-phenyl B-amino-pyrimidine 2-isoamylamino 4-chloro 6-chlorophenylamirio pyrimidine 2-chloro 4-amylamino d-cyclohexyiamino pyrimidine 1 2-ch1oro 4-n-hexylamino d-xenyiamino pyrimidine . b-chlorocyciohexenyl G-naphthylamino pyrimidine 2-chloro 4-chlorocyclopentylamino pyrimidine 2-dichloroanilino pyrimidine 2-chioro 4-amino d-chloroxenylamino pyrimidine 4-chloro 5-tolyl G-propylamino Para hydroxyphenyl (chloroethyl) carbamyl 6-toluido Alpha- (para-hydroxy 2-chioro -ethylphenylamino S-naphthyl G-xylldino pyrimidine 2-chloro 4-isopropylanilino 5-benzyl B-benzylamino pyrimidine Z-bromo 4-phenethylamino 5-(2'-butenyl) fi-cyclopentenylamino pyrimidine 2-chloro 4,6-diamino S-bromotolyl pyrimidine 2-bromo 4-amino 5-phenylisopropyl 6-chlorocyclohexylamino pyrimidine 2-chloro 4-bromonaphthylamino 6 pyrimidine 2-chloro 4,6-diamino 5-phenylpropyl pyrimidine 2-chloro 4-bromoethylamino B-chlorobutyl- 6- chlorobenzylamino pyrimidine 2-chloro 4-amino 5-chloroethylphenyl 6-sec.-

butylamino pyrimidine 1 v 2-iodo d-amino fi-bromoethylamino pyrimidine Z-bromo 4-dichloroanilino fi-chloroethylamino pyrimidine B-chloro 4-bromotoluido fi-benzylamino pyrimidine -isobutylamino 2-chloro 4-aminoanilino G-ethylamino pyrimi- G-phenylpropyl- Illustrative examples of hydroxycarbocyclicalkanes and of hydroiwcarbocyclic-thiocarbamyl may be used, depending upon the particular endproduct desired, are:

Para-hydroxyphenyl-carbamyl mercapto methane 7 Alpha- (para hydroxyphenyl carbamyl) beta .mercapto ethane w Alpha -(meta hydroxyphenyl-carbamyl) alphamercapto ethane Alpha-(para-hydrorwphenyl thiocarbamyl) aipha-mercapto pentane Ortho-hydroxyphenyl-(methyl)-carbamyl mercapto methane Alpha-(4-hydroxynaphthyl-[1] mercapto butene -carbamyl) betaalpha-ethyl beta-phenyl beta-mercapto ethane Hydroxytolyl carbamyl cyclopentyl mercapto methane Hydroxytolyl- (butyl) ane Para-hydroxyphenyl (cyclopentyl) thlocarbamyl mercapto methane mercapto methane 4-hydroxycyclohexyl (phenyl) capto methane 3-hydroxycyclopentyl-carbamyl tolyl. mercapto methane carbamyl mer- Alpha [para hydroxy' chlorophenyl (bromophenyl) thiocarbambyl] alpha ehlorocyclohexenyl beta-mercapto ethane Aipha-[hydroxy bromo cyclopentyl- (xenyll carbamyl] aipha-(chloroxylyl) beta-inercapto' I ethane I Alpha- (para-hydroxyphenyl carbamyl) alpha.-

mercapto omega-chloro pentane Hydroxycyclohexenyl (phenyiisopropyl) car-- barnylcyclopentenyl mercapto methane Alpha- [para-hydroXy enyl bamyl] beta-naphthyl beta-mercapto ethane -mercapto alkanes that chloro phenyl-carbamyli I -carbamyl mercapto meth- I v (butylphenyl) .w.

Alpha- [para-hydroxy chloro' phenyl- (isopentyl) thiocarbamyl] alpha-ethyl alpha-tolyl betaphenyl beta-mercapto ethane In order that those skilled in the art better may understand how the present invention may be carried into effect, the following illustrative examples are given. All parts are by weight.

Example 1 This example illustrates the preparation of 4,6- diamino pyrimidyl-2 para-hydroxyphenyl-carbamyl-methyl sulfide, the formula for which is 1V 4TH:

i if mN-o CSCHzC-NHOOH Parts 2-mercapto 4,6-diamino pyrimidine 142 Para-(chloroacetamido) phenol 185 Sodium hydroxide 40 The sodium hydroxide was dissolved in 1,000 parts water and the 2-mercapto 4,6-diamino pyrimidine was then added. The mixture was stirred until a clear solution resulted. The para-(chloroacetamido) phenol (para hydroxyphenyl-carbamyl chloro methane) was added to this solution and the resulting mixture then was heated on a steam plate. A visible reaction was noticeable. Alter heating for a short period, the reaction vessel was removed from the steam plate and the reaction was allowed to continue at room temperature for several hours while stirring. A precipitate settled from the reaction solution on standing. The precipitated solid comprising 4,6- diamino pyrimidyl-2 para-hydroxyphenyl-carbamyl-methyl sulfide was removed by filtration and then washed free of soluble salts. The residue was dried for several hours. The yield of dried product was approximately 92% of the theoretical amount obtainable.

The para-(chloroacet-amido) phenol used as a reactant in preparing the compound of this example is a very powerful vesicant. In marked contrast the 4,6-diamino pyrimidyl-2 para-hydroxyphenyl-carbamyl-methyl sulfide has little or no irritating characteristics. a

When the sodium hydroxide (hydrohalide acceptor) is employed in substantially larger amount than that used in the above formula, the sodium salt 01' the 4,6-diamino pyrimidyl-Z parahydroxyphenyl-carbamyl-methyl sulfide forms as an intermediate product. The desired hydroxy derivative then is obtained by adding an acid, for example hydrochloric acid, to the solution of this sodium salt in an amount sufllcient to render the solution neutral to litmus.

Example 2 Example 3 4,6-diamino pyrimidyl-2 para-hydroxyphenylthiocarbamyl-methyl sulfide is produced in essentially the same manner as set forth under Example 1 with the exception that, instead oi para-(chloroacetapiido) phenol, an equivalent amount of para-(chlorothioacetamido) phenol is em loyed.

Example 4 4,6-di-(methylamino) pyrimidyl-2 para-hydroxyphenyl-carbamyl-methyl sulfide is prepared in essentially the same manner as described under Example 1 with the exception that, instead of 2-mercapto 4,6-diamino pyrimidine, an equivalent amount of Z-mercapto 4,6-di- (methylamino) pyrimidine is employed.

Example 5 This example illustrates the preparation of 4,6- diamino pyrimidyl-2 ortho-hydroxylphenyl-carbamyl-methyl sulfide.

Parts 2-mercapto 4.6-diamino pyrimidine 142 Ortho-(chloroacetamido) phenol 185 Sodium hydroxide 43 The above components were added to 2,500 parts cold water. The mixture was stirred thoroughly for 3 hours. A visible reaction was noticeable and a solid precipitate formed. The precipitated solid comprising 4,6-diamino pyrimidyl-2 ortho-hydroxyphenyl-carbamyl-methyl zvas removed by filtration and then washed free I soluble salts. The residue was dried for several hours. The yield of dried product was approximately 90% oi' the theoretical amount obtainable.- The compound of this example, like the product of Example 1, lacked the vesicant characteristics 01 the ortho-(chloroacetamido) phenol from which it was prepared.

When the sodium hydroxide is employed in substantially larger amount than that used in the above formula, the sodium salt of the 4,6- diamono pyrimidyl-2 ortho-hydroxyphenyl-carbamyl-methyl sulfide is formed as an intermediate product. The desired hydroxy derivative then is obtained by adding an acid, for example hydrochloric acid, to the solution oi. this sodium salt in an amount sufilcient to render the solution neutral to litmus.

Example 7 4,6-diamino pyrimidyl-2 ortho-hydroxytolylcarbamyl-methyl sulfide is prepared in essentially the same manner as described under Example 2 with the exception that, instead of ortho- (chloroacetamido) phenol, an equivalent amount or ortho-hydroxytolyl-carbamyl chloro methane is employed.

Illustrative examples of other compounds of this invention, and which may be prepared as hereinbefore described are:

4,6-diamino pyrimidyl-2 meta-hydroxyphenylcarbamyl-methyl sulfide 2,6-diamino pyrimidyl-4 ortho-hydroxyphenylcarbamyl-methyl sulfide.

2,6-diamino pyrlmidyl-4-meta-hydroxyphenylcarbamyl-methyl sulfide 4,6-diamino pyrimidyl-2 ortho-hydroxyphenylthiocarbamyl-methyl sulfide two or three sulfur atoms are attached directly to a carbon atom of the diazine nucleus, thus:

It also will be understood that both the diazinyl monoandpoly-hydroxy (e. g., di-hydroxy, trihydroxy) carbocyclic-carbamyland thiocarbamyl-methyl and --ethyl sulfides may be prepared as hereinbefore described.

What I claim as new and desire to secure by Letters Patent of the United States is:

1. Chemical compounds corresponding to the general formula where n represents an integer and is at least 1 and not more than 2, Z represents a member of the class consisting of oxygen and sulfur, Y represents a divalent carbocyclic radical, and R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halo-hydrocarbon radicals.

2. Chemical compounds as in claim 1 wherein R represents hydrogen.

3. Chemical compounds as in claim 1 wherein R represents hydrogen, Z represents a member of the class consisting of oxygen and sulfur, and

'nisl.

4. Chemical compounds corresponding to the general formula where n represents an integer and is at least 1 and not more than 2, Z represents a member of the class consisting of oxygen and sulfur, Y represents a divalent carbocyclic radical, and R. represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halo-hydrocarbon radicals.

5. Chemical compounds corresponding to the general formula where Y represents a divalent carbocyclic radical, and R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halo-hydrocarbon radicals.

6. A diamino pyrimidyl hydroxycarbocycliccarbamyl-methyl sulfide.

7. A diamino pyrimidyl hydroxyphenyi-carbamyl-methyl sulfide. 5 8. 4,6-diamino pyrimidyl-2 phenyl-carbamyl-methyl sulfide.

9. 4,6-diamino pyrimidyl-2 phenyl-carbamyl-methyl sulfide.

10. A diamino pyrimidyl hydroxytolyl-carl0 bamyl-methyl sulfide.

11. A 4,6-diamino pyrimidyl-2 hydroxytolylcarbamyl-methyl sulfide.

12. The method of preparing chemical compounds corresponding to the general formula ortho-hydroxypara-hydroxywhere n represents an integer and is at least 1 and not more than,2, Z represents a member of the class consisting of oxygen and sulfur, Y represents a divalent carbocyclic radical, and R represents a member of the class consisting of hydrogen and monovalent hydrocarbon and halohydrocarbon radicals, said method comprising effecting reaction, in the presence of a hydrohalide acceptor, between (1) a mercapto pyrimidine corresponding to the general formula R-C N (mm (l3 -su L g l where R has the meaning above given, and (2) a haiide corresponding to the general formula 16. The method of preparing 4,6-diamino pyrimidyl-2 ortho-hydroxyphenyl-carbamyi-methyl sulfide which comprises effecting reaction, in the presence of an alkali-metal hydroxide, between 2-mercapto 4,6-diamino pyrimidine and ortho- (chloroacetamido) phenol.

GAETANO F. DALELIO. 

